1. Field of the Invention
The invention is directed toward a novel process by which hygroscopic salts of (−)-hydroxycitric acid, either potassium (−)-hydroxycitrate, the preferred salt of (−)-hydroxycitric acid, or, alternatively, sodium or other hygroscopic salts of (−)-hydroxycitric acid, can be rendered suitable for tableting, encapsulation and use in dry media such as powders in meal replacements for weight loss and other pharmaceutical purposes. Furthermore, the product of this invention can be made nonreactive as a part of acidic drink mixes and acidic snack bars. This invention is further directed toward the production of controlled release versions of potassium, sodium or other salts of (−)-hydroxycitric acid which can be used to provide controlled release of the compound.
2. Description of Prior Art
(−)-Hydroxycitric acid (abbreviated herein as HCA) a naturally-ocurring substance found chiefly in fruits of the species of Garcinia, and several synthetic derivatives of citric acid have been investigated extensively in regard to their ability to inhibit the production of fatty acids from carbohydrates, to suppress appetite, and to inhibit weight gain. (Sullivan, A. C., et al., American Journal of Clinical Nutrition 1977;30:767.) Numerous other benefits have been attributed to the use of HCA, including, but not limited to an increase in the metabolism of fat stores for energy and an increase in thermogenesis (the metabolism of energy sources to produce body heat in an otherwise wasteful cycle). One commonly offered explanation for the effects of HCA is that this compound inhibits the actions of cytoplasmic (cytosolic) ATP:citrate lyase. (D. Clouatre and M. E. Rosenbaum, The Diet and Health Benefits of HCA (Hydroxicitric Acid), 1994.) Weight loss benefits are ascribed to HCA, its salts and its lactone in U.S. Pat. No. 3,764,692 granted to John M. Lowenstein in 1973. Lowenstein described a variety of possible pharmaceutical salts of HCA based upon alkali metals, e.g., potassium and sodium, and alkaline earth metals, e.g., calcium and magnesium. The production of the potassium salt of HCA had been described in the scientific literature previous to Lowenstein's patent, but not in regard to its weight-loss properties. Research into HCA by scientists at the pharmaceutical firm of Hoffmann-La Roche revealed that the lactone form of HCA is far less effective than is the sodium salt of HCA for weight loss purposes, in part because the lactone form lacks the proper affinity for the receptor which is the target of the actions of HCA. However, the sodium salt has disadvantages for long-term administration, both because sodium possesses no positive metabolic effects with regard to obesity and because sodium has potential hypertensive actions as well as other drawbacks. Potassium, as a ligand for HCA, does not possess the disadvantages associated with sodium. Moreover, the absorption of the potassium salt of HCA is considered to be superior to that of the sodium salt owing to the greater rate of uptake of potassium in relation to sodium in most tissues.
Free (−)-hydroxycitric acid, calcium, magnesium and potassium salts of HCA and poorly characterized mixtures of two or more of these minerals, usually substantially contaminated with sodium, currently exist on the American market. Calcium/sodium salts have been sold widely since at least as early as 1994. Most of the HCA sold consists of calcium salts of varying purity. Aside from the potassium salt, all of these HCA forms suffer from problems in assimilation, a fact attested to by poor performance in controlled weight loss trials. For instance, the free acid form of (−)-hydroxycitric acid is extremely ionic and does not pass readily through the gut membranes. Free HCA has several further disadvantages. It undergoes rapid lacontonization, and, again, the lactone form has no appreciable physiological activity. Indeed, inclusion of any of the currently available mineral salts of HCA in a prepared beverage of acidic pH will lead to the development of the HCA lactone over time. The free acid form, moreover, has a tendency to be bound up and made unavailable to the body by soluble and insoluble fibers as well as by many other compounds. Likewise the potassium and sodium salts, if placed even only briefly in acidic or flavored beverages, typically will undergo color change or exhibit other signs of having undergone chemical interaction with the contents of the beverage. Finally, although there is some evidence to the effect that the free acid (not the lactone) is more active than is the calcium salt of HCA, there is also good evidence that the free acid and the lactone both are irritating to the GI-tract if consumed regularly in large amounts. Thus although a patent exists for the use of free (−)-hydroxycitric acid concentrate in food products (U.S. Pat. No. 5,536,516), the art taught therein offers no particular advantages for weight loss nor for other medicinal purposes.
The calcium and magnesium salts of HCA are poorly absorbed from the gastrointestinal tract because they are poorly soluble in aqueous media and because both of these minerals are saponified by bile acids and fats in the gut and/or are bound up by soluble and insoluble fibers or other substances in the diet or secreted during digestion. Some of these problems have been pointed out by medical researchers and admitted in print by at least one primary manufacturer of HCA products. (Heymsfield, Steven B, et al. JAMA 1998;280(18):1596–1600; Letters, JAMA 1999;282:235.) Moreover, there is no evidence that merely making calcium and magnesium salts of HCA more soluble, such as can be accomplished by adding small amounts of potassium and/or sodium and/or lactone, will solve the problem of assimilation. HCA is known to have three separate binding points, and simple chemical experimentation quickly shows that divalent ions, such as those of calcium and magnesium, cannot be readily separated by the application of other acids, such as human gastric acid, from the HCA once these minerals have been reacted with it. The action of stomach acid, however, may free one of the two valences of calcium or magnesium for attachment to fats, bile acids, gums, fibers, pectins, and so forth and so on, which is an undesirable outcome. For weight loss and other purposes, a minimally effective amount of HCA derived from its calcium salt requires the administration of between 12 and 15 grams of a 50% material, and this amount of calcium (−)-hydroxycitrate may lead to undesirably elevated levels of binding and excretion of other dietary minerals, such as zinc, aside from presenting difficulties in administration. Animal trials (not published) have further demonstrated that in order for the potassium salt to be maximally effective, the ligand must be fully bound to the HCA with only trivial amounts of contaminants, including other minerals or fibers or sugars. Hence the calcium and magnesium salts, either alone or in the form of various mixtures together or in combination with the potassium and sodium salts, are not preferred delivery forms for HCA.
Several recent international patent applications and at least one U.S. patent claim to have greatly improved the efficacy of HCA via its delivery as calcium, magnesium and admixtures of salts. For instance, WO 99/03464, filed 28 Jan. 1999, claims special benefits for “hydroxycitric acid compositions which comprise approximately 14 to 26% by weight of calcium, and approximately 24 to 40% by weight of potassium or approximately 14 to 24% by weight of sodium, or a mixture thereof, each calculated as a percentage of the total hydroxycitric acid content of the composition, together with dietary supplements and food products containing such compositions and methods for utilizing such compositions, dietary supplements and food products to reduce body weight in mammals are disclosed.” However, research performed specifically with this compound showed that its assimilation is very poor even when taken on an empty stomach (Loe Y C, Bergeron N, Rodriguez N, Schwarz J M. Gas chromatography/mass spectrometry method to quantify blood hydroxycitrate concentration. Anal Biochem. 1, 2001 May 1;292(1):148–54) and that eating a meal shortly after taking it reduced its absorption by about 60%. (Loe Y, Bergeron N, Phan J, Wen M, Lee J, Schwarz J-M, Time Course of Hydroxycitrate Clearance in Fasting and Fed Humans, FASEB Journal, 15,4:632, Abs. 501.1, 2001.)
No proof is offered in WO 99/03464 that the proposed compound is superior to fully reacted calcium HCA with regard to assimilation. It also should be noted that inasmuch as Garcina cambogia is typically salted for drying in Asia with the subsequent extracts including large amounts of sodium and inasmuch as calcium salts of HCA have been sold in the U.S. since at least 1992, the realization that mixing a divalent ligand with a monovalent ligand in reacting HCA will yield a soluble, yet increasingly nonhygroscopic salt was known at least as far back as 1992. Several of the early Indian-supplied “potassium” salts were, in fact, mixtures of calcium, potassium and sodium (−)-hydroxycitrate. Of course, the amount of sodium allowed with this product will be in excess of that allowed on low sodium diets and additional sodium is ill-advised on any modern diet.
Another application by the same inventor as above, WO 00/15051, seeks to make calcium (−)-hydroxycitrate soluble by under-reacting the material, i.e., leaving a substantial amount of HCA lactone in the finished product. This procedure, however, does little to improve the uptake of HCA. The problems with the lactone are discussed above, and the lactone in large amounts is known to be irritating. (Ishihara K, Oyaizu S, Onuki K, Lim K, Fushiki T. Chronic (−)-hydroxycitrate administration spares carbohydrate utilization and promotes lipid oxidation during exercise in mice. J Nutr. 2000 December;130(12):2990–5.) Making calcium soluble, again, does nothing to prevent its saponification in the gut nor does this improve the general rate of assimilation of calcium. One must assume that the rate of uptake by the compound taught in this invention will be even worse than that tested by Loe Y, et al., as indicated with WO 99/03464 above. In any event, the process proposed in WO 00/15051 was anticipated by others and had already been published in English in 1997 (Sawada, H., et al. Effects of liquid garcinia extract and soluble garcinia powder on body weight change. Journal of Japan Oil and Chemicals/Nihon Yukagaku Kaishi 1997 December;46, 12:1467–1474) and many months earlier in Japanese.
A much more promising application is WO 02/014477, first applied for in 17 Aug. 2000, which relates to a composition comprising hydroxycitric acid (HCA) in combination with either one or both of garcinol and anthocyanin. However, one should note that the effects reported are not overwhelming. In eight weeks, the average weight loss, for instance, was 4 pounds versus 2.5 pounds for control. Using a higher dosage of potassium (−)-hydroxycitirate alone, Clouatre et al. in U.S. Pat. No. 6,447,807 reported an average weight loss over a three week period of 3 pounds per week. Still to be determined is whether the additive effect shown in WO 02/014477 extends beyond the mild response reported if higher dosages of either component are ingested. Moreover, in practice garcinol is a common contaminant of HCA products, hence this application is claiming a special virtue for a compound already typically present in the salts which have been used for clinical studies, i.e., extracts rather than synthesized pure (−)-hydroxycitric acid.
Finally, U.S. Pat. No. 6,221,901 discusses the preparation and employments of magnesium (−)-hydroxycitirate. Leaving aside the many difficulties with the claims of this patent, the dosages used to achieve the indicated results were massive. To achieve a hypotensive effect, for instance, the inventors fed their animals 500 mg/kg magnesium (−)-hydroxycitirate. Using the standard 5:1 multiplier for rat to human data, the dose of magnesium hydroxycitrate employed by Shrivastava et al. is equivalent to a human ingesting 100 mg/kg/day or 7 grams for the average-sized human subject. Of this amount, 45% would be elemental magnesium, hence we have the equivalent of a human ingesting approximately 3.15 grams of magnesium. The Recommended Dietary Allowances, 10th edition (National Research Council, 1989), indicates that most humans begin to suffer diarrhea at more than 350 mg/day. In other words, the test dose used by Shrivastava et al. is nearly 10 times the dose at which side effects would normally be expected to begin to appear. The diarrhea induced itself would lower blood pressure rapidly. Hence, with normal magnesium (−)-hydroxycitirate not only is there poor uptake, but also there is the danger of osmotic diarrhea. Clearly this compound is not the answer to issues of improving the delivery of (−)-hydroxycitirate.
The preferred salt of HCA for pharmaceutical use is potassium (−)-hydroxycitrate (abbreviated herein as KHCA). The mineral potassium is fully soluble, as is its HCA salt, and is known to possess cell membrane permeability which is 100 times greater than that possessed by sodium. However, the potassium salt of HCA, as is also true of the sodium salt, is extremely hygroscopic and thus not suitable under normal circumstances for the production of dry delivery forms. In drawing moisture to itself, KHCA will also tend to bind to available binding sites of compounds in its immediate environment, and this action often later will markedly impede the assimilation of KHCA from the gut. KHCA is also not suitable for liquid delivery forms inasmuch as KHCA in solution will slowly lactonize to an equilibrium which is dependent upon the pH. One recent patent (U.S. Pat. No. 5,783,603) does teach a technique for the production of KHCA, but this material is nonhygroscopic only under the conditions mentioned specifically in that patent, to wit, “milling, sifting, blending and packing said dried precipitate under nitrogen to obtain said potassium hydroxycitric acid [sic] composition.” If left in the open air outside of a humidity-controlled environment, the KHCA produced according to that patented method will begin to absorb moisture within a few minutes. Except as a very minor ingredient, it cannot be used as a component of dry pharmaceutical or nutriceutical preparations.
Only one piece of prior art (the present inventors' own U.S. Pat. No. 6,447,807) teaches a method for making the hygroscopic salts of hydroxycitric acid workable, and that invention proposes a method distinct from that contained herein. No other prior art teaches the production of the relatively pure potassium salt of (−)-hydroxycitric acid in a form which is workable under those conditions necessary for tableting, encapsulation, the production of controlled release vehicles nor incorporation into dry powders, such as dry meal replacement mixes. No other prior art teaches a method of including potassium or other forms of HCA in liquid media without lactonization and no other prior art teaches a method by which KHCA may be delivered under controlled release. Likewise, no other prior art teaches the above with regard to sodium (−)-hydroxycitrate.
The lack of a method of producing a controlled release form of HCA, regardless of the salt used, has led to a problem in the delivery of the drug. Tests performed to establish the appetite-suppressing effects of HCA found that a single large oral dose or two divided oral doses totaling one fourth the size of the single dose resulted in a 10% or greater reduction in food consumption in experimental animals fed a high-sugar diet. This result continued over many weeks with the chronic ingestion of HCA. The requirement for at least two divided doses of HCA for efficacy is the only thoroughly established procedure to date.
Giving HCA as multiple doses, as is true of any drug, is inconvenient and is not supported by good patient compliance. Multiple doses given in the form of any of the current salts is also wasteful in that any material delivered to the body which is above the baseline or threshold necessary to produce benefits is simply an excess which is excreted. Controlled release of HCA would avoid both excess and waste, on the one one, and gaps in coverage, on the other hand. Controlled release makes it possible to simplify the dosage schedule to one daily administration. Moreover, it is to be expected that a smaller amount of HCA delivered by controlled release will provide benefits which are superior to those found with a larger amount of HCA supplied after a normal fashion in at least two dosages.